Recruitment of FBXO22 for targeted degradation of NSD2.

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.

Recruitment of FBXO22 for Targeted Degradation of NSD2.

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here, we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain of function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 in a covalent and reversible manner to recruit the SCF FBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCF FBXO22 . Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.

Assessment of spring water quality of Khandbari Municipality in Sankhuwasabha District, Eastern Nepal.

The study was carried out in the Khandbari Municipality, Sankhuwasabha District, Eastern Nepal to document the spring location and assess the water quality of the spring water for drinking and irrigation purposes. A total of 85 springs were mapped, which are located from 274 to 2176 m in altitude. Spring water samples were collected from 33 springs in the pre-monsoon (November, 2021) and 31 springs in the post-monsoon (March, 2022). Correlation matrices, t-test, principal component analysis (PCA), Piper diagram, Gibbs diagram, water quality index (WQI), United States Salinity Laboratory (USSL) diagram, and Wilcox diagram were applied for evaluating the spring water. All the physicochemical parameters were within the Nepalese National Drinking Water Quality Standard (NDWQS) and drinking water quality guidelines of the World Health Organization (WHO) except for pH in the pre-monsoon and iron in the post-monsoon season. The main contributors to the groundwater are Na+, Ca2+, Cl-, total dissolved solids (TDS), and total hardness, which exhibit significant correlations with electrical conductivity (EC) similar to TDS, suggesting their common source of origin. Based on the WQI, spring water is excellent in the post-monsoon and excellent and good in the pre-monsoon season. Furthermore, the spring water is excellent for irrigation purposes except for the percent sodium in the post-monsoon and the magnesium ratio in the pre-monsoon season. Gibbs diagram illustrates that spring water is mainly governed by rock and precipitation dominance in some springs. The PCA indicates that anthropogenic activities (mixing of human waste and agricultural run-off in the spring water) are the main causes of contamination. Piper trilinear diagram demonstrates carbonate dissolution and silicate weathering as major processes for controlling the spring water chemistry. The study reveals that 62.5% of spring water was contaminated with microbes. For benthic macroinvertebrates, 18 springs were sampled, where nine orders and 17 families were recorded in the pre-monsoon and six orders and ten families in the post-monsoon season. The main influencing variables for macroinvertebrate assemblages are elevation, discharge, NO3-, and NH3.

Cardiac Substructure Radiation Dose and Risk of Late Cardiac Disease in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

PURPOSE: Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished. METHODS: Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships. RESULTS: The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6 [95% CI, 1.6 to 4.1]) and left ventricle (RR, 2.2 [95% CI, 1.3 to 3.7]) increased risk of CAD, and to the tricuspid valve (RR, 5.5 [95% CI, 2.0 to 15.1]) and right ventricle (RR, 8.4 [95% CI, 3.7 to 19.0]) increased risk of VD. CONCLUSION: Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.

Cardiac Disease in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Radiation therapy (RT) is an essential component in the treatment of many pediatric malignancies. Thoracic RT may expose the heart to radiation dose and thereby increase the risk of late cardiac disease. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on late cardiac disease in survivors of childhood cancer treated with RT. METHODS AND MATERIALS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We identified 1496 articles; 4 were included for dose-response modeling between mean cardiac radiation dose and risk of late coronary artery disease, heart failure (HF), valvular disease, and any cardiac disease. RESULTS: For each 10-Gy increase in corrected mean cardiac radiation dose in 1.8- to 2.0-Gy fractions, we estimated a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25) for coronary artery disease, of 1.87 (95% CI, 1.70-2.06) for HF, of 1.87 (95% CI, 1.78-1.96) for valvular disease, and of 1.88 (95% CI, 1.75-2.03) for any cardiac disease. From the same model, for each 100-mg/m2 increase in cumulative anthracycline dose, the hazard ratio for the development of HF was 1.93 (95% CI, 1.58-2.36), equivalent to an increase in mean heart dose of approximately 10.5 Gy. Other nontreatment factors were inconsistently reported in the analyzed articles. CONCLUSIONS: Radiation dose to the heart increases the risk of late cardiac disease, but survivors of childhood cancer who receive a mean dose <10 Gy at standard fractionation are at low absolute risk (<∼2% approximately 30 years after exposure) of late cardiac disease in the absence of anthracycline exposure. Minimizing cardiac radiation dose is especially relevant in children receiving anthracyclines. When cardiac sparing is not possible, we recommend prioritizing target coverage. It is likely that individual cardiac substructure doses will be a better predictor of specific cardiac diseases than mean dose, and we urge the pediatric oncology community to further study these relationships.

Strategies in the Management of Pancreatic Ductal Adenocarcinoma Involving Aberrant Right Hepatic Artery Arising From the Superior Mesenteric Artery.

Introduction The prevailing guidelines do not include the involvement of an aberrant right hepatic artery (aRHA) arising from the superior mesenteric artery in classifying borderline resectable pancreatic ductal adenocarcinoma (BR PDAC). Our novel classification aims to distinguish different entities depending on the location and degree of tumor involvement of aRHA and propose a strategy to manage tumor involvement of aRHA in PDAC. Material and methods The patients who underwent pancreaticoduodenectomy (PD) from September 1, 2018, to August 31, 2022 were analyzed retrospectively, and patients with aRHA were included in the study. Depending on the radiological data, arterial involvement of the aRHA was classified into group I with proximal involvement of the aRHA up to 2 cm from its origin in the superior mesenteric artery (SMA) and group II with distal involvement of aRHA beyond 2 cm from its origin in SMA. In addition, the resection margin status was correlated with the technique employed for managing the tumor-involved artery. Results A total of 122 patients underwent PD during the study period. Eight patients were identified to have tumor involvement of the aRHA arising from the SMA. Among the five patients in group I, three patients who had upfront surgery showed R1 resection regardless of periarterial divestment or resection/reconstruction of the involved artery, whereas R0 resection was achieved in the two patients who had neoadjuvant therapy. All patients in group II had R0 resection regardless of receiving neoadjuvant therapy. There were no significant morbidity and mortality in our series. Conclusion The aRHA should be considered in the classification of BR PDAC. Management strategies should be tailored based on the location and the degree of tumor involvement in the aRHA. We advocate neoadjuvant therapy for proximal involvement and upfront surgery for distal involvement of aRHA to achieve good oncological clearance.

Development and validation of a population-based anatomical colorectal model for radiation dosimetry in late effects studies of survivors of childhood cancer.

PURPOSE: The purposes of this study were to develop and integrate a colorectal model that incorporates anatomical variations of pediatric patients into the age-scalable MD Anderson Late Effects (MDA-LE) computational phantom, and validate the model for pediatric radiation therapy (RT) dose reconstructions. METHODS: Colorectal contours were manually derived from whole-body non-contrast computed tomography (CT) scans of 114 pediatric patients (age range: 2.1-21.6 years, 74 males, 40 females). One contour was used for an anatomical template, 103 for training and 10 for testing. Training contours were used to create a colorectal principal component analysis (PCA)-based statistical shape model (SSM) to extract the population's dominant deformations. The SSM was integrated into the MDA-LE phantom. Geometric accuracy was assessed between patient-specific and SSM contours using several overlap metrics. Two alternative colorectal shapes were generated using the first 17 dominant modes of the PCA-based SSM. Dosimetric accuracy was assessed by comparing colorectal doses from test patients' CT-based RT plans (ground truth) with reconstructed doses for the mean and two alternative models in age-matched MDA-LE phantoms. RESULTS: When using all 103 PCA modes, the mean (min-max) Dice similarity coefficient, distance-to-agreement and Hausdorff distance between the patient-specific and reconstructed contours for the test patients were 0.89 (0.85-0.91), 2.1 mm (1.7-3.0), and 8.6 mm (5.7-14.3), respectively. The average percent difference between reconstructed and ground truth mean and maximum colorectal doses for the mean (alternative 1, 2) model were 6.3% (8.1%, 6.1%) and 4.4% (4.3%, 4.7%), respectively. CONCLUSIONS: We developed, validated and integrated a colorectal PCA-based SSM into the MDA-LE phantom and demonstrated its dosimetric performance for accurate pediatric RT dose reconstruction.

Minimally-Invasive Plate Osteosynthesis for Clavicle Fractures.

Objective To analyze the radiological, clinical, and functional outcomes of clavicle fractures treated with the minimally-invasive plate osteosynthesis (MIPO) technique. Methods From June 2018 to July 2019, 17 cases of clavicular fractures were managed using the MIPO technique under C-arm fluoroscopy. The functional outcomes were assessed using the Constant-Murley score and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. The clinical results of union, the complications, the operative time, the hospital stay, as well as infection, were analyzed. Results The mean follow-up time was of 10.41 ± 1.75 months (range: 8 to 14 months). There were 11 male and 6 female patients, with a mean age of 39.05 ± 10.76 years (range: 22 to 57 years). All fractures united on the mean time of 15.35 ± 3.08 weeks (range: 12 to 20 weeks). The mean operative time was of 98.11 ± 13.83 minutes (range: 70 to 130 minutes), and the mean length of the hospital stay was of 4.7 ± 1.12 days (range: 3 to 7 days). The mean Constant-Murley score was of 74.82 ± 6.36 in 4 th postoperstive month, and of 92.35 ± 5.48 in the 8 th postoperative month, which was statistically significant. The mean DASH score was of 9.94 ± 1.55 in the 4 th postoperative month, and of 5.29 ± 1.85 in the 8 th postoperative month, which was also statistically significant. One patient had superficial skin infection at the site of the incision. Conclusions The MIPO technique is an alternative method for the fixation of clavicle fractures, but it is technically more demanding, and requires well-equipped operating room facilities.

Stray neutron radiation exposures from proton therapy: physics-based analytical models of neutron spectral fluence, kerma and absorbed dose.

Objective. Patients who receive proton beam therapy are exposed to unwanted stray neutrons. Stray radiations increase the risk of late effects in normal tissues, such as second cancers and cataracts, and may cause implanted devices such as pacemakers to malfunction. Compared to therapeutic beams, little attention has been paid to modeling stray neutron exposures. In the past decade, substantial progress was made to develop semiempirical models of stray neutron dose equivalent, but models to routinely calculate neutron absorbed dose and kerma are still lacking. The objective of this work was to develop a new physics based analytical model to calculate neutron spectral fluence, kerma, and absorbed dose in a water phantom.Approach. We developed the model using dosimetric data from Monte Carlo simulations and neutron kerma coefficients from the literature. The model explicitly considers the production, divergence, scattering, and attenuation of neutrons. Neutron production was modeled for 120-250 MeV proton beams impinging on a variety of materials. Fluence, kerma and dose calculations were performed in a 30 × 180 × 44 cm3phantom at points up to 43 cm in depth and 80 cm laterally.Main Results. Predictions of the analytical model agreed reasonably with corresponding values from Monte Carlo simulations, with a mean difference in average energy deposited of 20%, average kerma coefficient of 21%, and absorbed dose to water of 49%.Significance. The analytical model is simple to implement and use, requires less configuration data that previously reported models, and is computationally fast. This model appears potentially suitable for integration in treatment planning system, which would enable risk calculations in prospective and retrospective cases, providing a powerful tool for epidemiological studies and clinical trials.

Minimally-Invasive Plate Osteosynthesis for Clavicle Fractures / Osteossíntese minimamente invasiva com placa para fraturas de clavícula

Abstract Objective To analyze the radiological, clinical, and functional outcomes of clavicle fractures treated with the minimally-invasive plate osteosynthesis (MIPO) technique. Methods From June 2018 to July 2019, 17 cases of clavicular fractures were managed using the MIPO technique under C-arm fluoroscopy. The functional outcomes were assessed using the Constant-Murley score and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. The clinical results of union, the complications, the operative time, the hospital stay, as well as infection, were analyzed. Results The mean follow-up time was of 10.41 1.75 months (range: 8 to 14 months). There were 11 male and 6 female patients, with a mean age of 39.05 10.76 years (range: 22 to 57 years). All fractures united on the mean time of 15.35 3.08 weeks (range: 12 to 20 weeks). The mean operative time was of 98.11 13.83 minutes (range: 70 to 130 minutes), and the mean length of the hospital stay was of 4.7 1.12 days (range: 3 to 7 days). The mean Constant-Murley score was of 74.82 6.36 in 4th postoperstive month, and of 92.35 5.48 in the 8th postoperative month, which was statistically significant. The mean DASH score was of 9.94 1.55 in the 4th postoperative month, and of 5.29 1.85 in the 8th postoperative month, which was also statistically significant. One patient had superficial skin infection at the site of the incision. Conclusions The MIPO technique is an alternative method for the fixation of clavicle fractures, but it is technically more demanding, and requires well-equipped operating room facilities.

Resumo Objetivo Analisar o resultado radiológico, clínico e funcional das fraturas da clavícula, tratadas pela técnica de osteossíntese com placa minimamente invasiva (MIPO). Métodos De junho de 2018 a julho de 2019, um total de 17 casos de fraturas claviculares foram tratadas com a técnica de osteossíntese com placa minimamente invasiva (MIPO), sob fluoroscopia com o braço em C. Os resultados funcionais foram avaliados por meio do escore de Constant-Murley e pelo escore de incapacidade do braço, ombro e mão (DASH). Foram analisados os resultados clínicos de consolidação, complicações, tempo cirúrgico, permanência hospitalar e infecção. Resultados O tempo médio de acompanhamento neste estudo foi de 10,41 1,75 meses (variação, 8 a 14 meses). Havia 11 pacientes do sexo masculino e seis do feminino, com média de idade de 39,05 10,76 anos (variação de 22 a 57 anos). Todas as fraturas se consolidaram no tempo médio de 15,35 3,08 semanas (variação, 12 a 20 semanas). O tempo cirúrgico médio foi de 98,11 13,83 minutos (variação, 70 a 130), sendo a permanência hospitalar média de 4,7 1,12 dias (variação de 3 a 7). O escore de Constant-Murley médio foi de 74,82 6,36 no 4° mês e 92,35 5,48 no 8° mês do pós-operatório, o que foi estatisticamente significativo. O escore DASH médio foi de 9,94 1,55 no 4° mês e 5,29 1,85 na 8ª semana do pós-operatório, também sendo estatisticamente significativo. Um paciente apresentou infecção cutânea superficial no local da incisão. Conclusões A técnica MIPO é um método alternativo para a fixação de fraturas da clavícula, porém é tecnicamente mais desafiador, já que necessita de instalações cirúrgicas mais bem equipadas.

Early Oral Feeding with Vascular Resection among Patients Undergoing Pancreatoduodenectomy in a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

INTRODUCTION: Pancreatoduodenectomy with vascular resection is performed in locally advanced periampullary malignancies. In our practice, early oral feeding is initiated in patients undergoing pancreatoduodenectomy. This study aims to find the prevalence of early oral feeding with vascular resection among patients undergoing pancreatoduodenectomy. METHODS: This was a descriptive cross-sectional study conducted among hospital records of 152 patients who underwent pancreatoduodenectomy in the department of surgery of a tertiary care hospital from 2016 to 2020. Ethical approval was taken from the Institutional Review Committee (Reference number: 0812202102). Convenience sampling was done. Patients clinical and sociodemographic data were collected and analyzed using Statistical Package for the Social Sciences version 20. Point estimate at 95% Confidence Interval was calculated along with frequency, percentage, mean, and median. RESULTS: Among 152 patients undergoing pancreatoduodenectomy, early oral feeding with vascular resection was done in 17 (11.18%) (6.17-16.19 at 95% Confidence Interval). Portal vein and superior mesenteric artery were resected in one (5.88%) and hepatic artery in one (5.88%) patient. Type I, III and IV reconstruction was done in nine (52.9%), five (29.41%) and one (5.88%) respectively. Clinically relevant delayed gastric emptying and postoperative pancreatic fistula were seen in two (11.7%). Complication of Clavien-Dindo Grade III or higher was seen in one (5.88%) patient. One (5.88%) mortality was noted. CONCLUSIONS: The prevalence of early oral feeding with vascular resection among patients undergoing pancreatoduodenectomy was similar to other studies done in similar settings. Early enteral feeding is well tolerated in patients undergoing pancreatoduodenectomy with vascular resection.

Body region-specific 3D age-scaling functions for scaling whole-body computed tomography anatomy for pediatric late effects studies.

Purpose.Radiation epidemiology studies of childhood cancer survivors treated in the pre-computed tomography (CT) era reconstruct the patients' treatment fields on computational phantoms. For such studies, the phantoms are commonly scaled to age at the time of radiotherapy treatment because age is the generally available anthropometric parameter. Several reference size phantoms are used in such studies, but reference size phantoms are only available at discrete ages (e.g.: newborn, 1, 5, 10, 15, and Adult). When such phantoms are used for RT dose reconstructions, the nearest discrete-aged phantom is selected to represent a survivor of a specific age. In this work, we (1) conducted a feasibility study to scale reference size phantoms at discrete ages to various other ages, and (2) evaluated the dosimetric impact of using exact age-scaled phantoms as opposed to nearest age-matched phantoms at discrete ages.Methods.We have adopted the University of Florida/National Cancer Institute (UF/NCI) computational phantom library for our studies. For the feasibility study, eight male and female reference size UF/NCI phantoms (5, 10, 15, and 35 years) were downscaled to fourteen different ages which included next nearest available lower discrete ages (1, 5, 10 and 15 years) and the median ages at the time of RT for Wilms' tumor (3.9 years), craniospinal (8.0 years), and all survivors (9.1 years old) in the Childhood Cancer Survivor Study (CCSS) expansion cohort treated with RT. The downscaling was performed using our in-house age scaling functions (ASFs). To geometrically validate the scaling, Dice similarity coefficient (DSC), mean distance to agreement (MDA), and Euclidean distance (ED) were calculated between the scaled and ground-truth discrete-aged phantom (unscaled UF/NCI) for whole-body, brain, heart, liver, pancreas, and kidneys. Additionally, heights of the scaled phantoms were compared with ground-truth phantoms' height, and the Centers for Disease Control and Prevention (CDC) reported 50th percentile height. Scaled organ masses were compared with ground-truth organ masses. For the dosimetric assessment, one reference size phantom and seventeen body-size dependent 5-year-old phantoms (9 male and 8 female) of varying body mass indices (BMI) were downscaled to 3.9-year-old dimensions for two different radiation dose studies. For the first study, we simulated a 6 MV photon right-sided flank field RT plan on a reference size 5-year-old and 3.9-year-old (both of healthy BMI), keeping the field size the same in both cases. Percent of volume receiving dose ≥15 Gy (V15) and the mean dose were calculated for the pancreas, liver, and stomach. For the second study, the same treatment plan, but with patient anatomy-dependent field sizes, was simulated on seventeen body-size dependent 5- and 3.9-year-old phantoms with varying BMIs. V15, mean dose, and minimum dose received by 1% of the volume (D1), and by 95% of the volume (D95) were calculated for pancreas, liver, stomach, left kidney (contralateral), right kidney, right and left colons, gallbladder, thoracic vertebrae, and lumbar vertebrae. A non-parametric Wilcoxon rank-sum test was performed to determine if the dose to organs of exact age-scaled and nearest age-matched phantoms were significantly different (p < 0.05).Results.In the feasibility study, the best DSCs were obtained for the brain (median: 0.86) and whole-body (median: 0.91) while kidneys (median: 0.58) and pancreas (median: 0.32) showed poorer agreement. In the case of MDA and ED, whole-body, brain, and kidneys showed tighter distribution and lower median values as compared to other organs. For height comparison, the overall agreement was within 2.8% (3.9 cm) and 3.0% (3.2 cm) of ground-truth UF/NCI and CDC reported 50th percentile heights, respectively. For mass comparison, the maximum percent and absolute differences between the scaled and ground-truth organ masses were within 31.3% (29.8 g) and 211.8 g (16.4%), respectively (across all ages). In the first dosimetric study, absolute difference up to 6% and 1.3 Gy was found for V15and mean dose, respectively. In the second dosimetric study, V15and mean dose were significantly different (p < 0.05) for all studied organs except the fully in-beam organs. D1and D95were not significantly different for most organs (p > 0.05).Conclusion.We have successfully evaluated our ASFs by scaling UF/NCI computational phantoms from one age to another age, which demonstrates the feasibility of scaling any CT-based anatomy. We have found that dose to organs of exact age-scaled and nearest aged-matched phantoms are significantly different (p < 0.05) which indicates that using the exact age-scaled phantoms for retrospective dosimetric studies is a better approach.

Self-inflicted stab injury with abdominal evisceration: A case report.

INTRODUCTION AND IMPORTANCE: Self-inflicted abdominal stab injury with an intention of self-harm is uncommon. Moreover, self-inflicted injury leading to avulsion of the colon has rarely been reported in the literature. We report a case of a 42-years-female with schizoaffective disorder who presented with self-inflicted stab injury on the abdomen resulting in abdominal evisceration. PRESENTATION OF CASE: A 42-years-female with schizoaffective disorder (F25) for 10 years presented to the emergency department with multiple, self-inflicted injuries on the abdomen. A large free portion of the omentum and segment of the bowel were brought in a plastic carry bag. Examination revealed multiple transverse hesitation cuts in the epigastrium and a single deep penetrating transverse cut resulting in the evisceration of the omentum and colon. Intra-operatively, avulsion of a large portion of the greater omentum and missing segment of the mid transverse colon was observed. The patient underwent an immediate abdominal exploration and side-to-side colo-colic anastomosis along with diversion ileostomy. At three months following primary surgery, ileostomy closure was done. CONCLUSION: Patients with schizophrenia spectrum psychosis are at risk of self-harm and in our case a schizoaffective patient presented with self-inflicted injuries that required an emergency abdominal exploration and repair. This case highlights a multi-disciplinary approach for the management of these cases and mandates clinicians and caregivers to be more vigilant to restrict injuries in the future.

Evolution of the folding landscape of effector caspases.

Caspases are a family of cysteinyl proteases that control programmed cell death and maintain homeostasis in multicellular organisms. The caspase family is an excellent model to study protein evolution because all caspases are produced as zymogens (procaspases [PCPs]) that must be activated to gain full activity; the protein structures are conserved through hundreds of millions of years of evolution; and some allosteric features arose with the early ancestor, whereas others are more recent evolutionary events. The apoptotic caspases evolved from a common ancestor (CA) into two distinct subfamilies: monomers (initiator caspases) or dimers (effector caspases). Differences in activation mechanisms of the two subfamilies, and their oligomeric forms, play a central role in the regulation of apoptosis. Here, we examine changes in the folding landscape by characterizing human effector caspases and their CA. The results show that the effector caspases unfold by a minimum three-state equilibrium model at pH 7.5, where the native dimer is in equilibrium with a partially folded monomeric (PCP-7, CA) or dimeric (PCP-6) intermediate. In comparison, the unfolding pathway of PCP-3 contains both oligomeric forms of the intermediate. Overall, the data show that the folding landscape was first established with the CA and was retained for >650 million years. Partially folded monomeric or dimeric intermediates in the ancestral ensemble provide mechanisms for evolutionary changes that affect stability of extant caspases. The conserved folding landscape allows for the fine-tuning of enzyme stability in a species-dependent manner while retaining the overall caspase-hemoglobinase fold.

Urinary FABP1 is a biomarker for impaired proximal tubular protein reabsorption and is synergistically enhanced by concurrent liver injury.

Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte- or in a PTEC-specific manner, or both. Upon administration of diphtheria toxin (DT), massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Radiation therapy related cardiac disease risk in childhood cancer survivors: Updated dosimetry analysis from the Childhood Cancer Survivor Study.

BACKGROUND AND PURPOSE: We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort. METHODS: We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20 = 0 ( [Formula: see text] ) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3-5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and [Formula: see text] (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable. RESULTS: Consistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10 Gy, V20 ≥ 0.1%, and [Formula: see text]  ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P < 0.05) increases in risk with updated dosimetry for Dm in the category of 20 to 29.9 Gy and V20 in the category of 30% to 79.9%. When changes in the linear dose-response relationship for Dm were assessed, the slopes of the dose response were steeper (P < 0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy. CONCLUSION: These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.

Development and validation of an age-scalable cardiac model with substructures for dosimetry in late-effects studies of childhood cancer survivors.

BACKGROUND AND PURPOSE: Radiation therapy is a risk factor for late cardiac disease in childhood cancer survivors. Several pediatric cohort studies have established whole heart dose and dose-volume response models. Emerging data suggest that dose to cardiac substructures may be more predictive than whole heart metrics. In order to develop substructure dose-response models, the heart model previously used for pediatric cohort dosimetry needed enhancement and substructure delineation. METHODS: To enhance our heart model, we combined the age-scalable capability of our computational phantom with the anatomically-delineated (with substructures) heart models from an international humanoid phantom series. We examined cardiac volume similarity/overlap between registered age-scaled phantoms (1, 5, 10, and 15 years) with the enhanced heart model and the reference phantoms of the same age; dice similarity coefficient (DSC) and overlap coefficient (OC) were calculated for each matched pair. To assess the accuracy of our enhanced heart model, we compared doses from computed tomography-based planning (ground truth) with reconstructed heart doses. We also compared doses calculated with the prior and enhanced heart models for a cohort of nearly 5000 childhood cancer survivors. RESULTS: We developed a realistic cardiac model with 14-substructures, scalable across a broad age range (1-15 years); average DSC and OC were 0.84 ± 0.05 and 0.90 ± 0.05, respectively. The average percent difference between reconstructed and ground truth mean heart doses was 4.2%. In the cohort dosimetry analysis, dose and dose-volume metrics were approximately 10% lower on average when the enhanced heart model was used for dose reconstructions. CONCLUSION: We successfully developed and validated an anatomically realistic age-scalable cardiac model that can be used to establish substructure dose-response models for late cardiac disease in childhood cancer survivor cohorts.

Caspases from scleractinian coral show unique regulatory features.

Coral reefs are experiencing precipitous declines around the globe with coral diseases and temperature-induced bleaching being primary drivers of these declines. Regulation of apoptotic cell death is an important component in the coral stress response. Although cnidaria are known to contain complex apoptotic signaling pathways, similar to those in vertebrates, the mechanisms leading to cell death are largely unexplored. We identified and characterized two caspases each from Orbicella faveolata, a disease-sensitive reef-building coral, and Porites astreoides, a disease-resistant reef-building coral. The caspases are predicted homologs of the human executioner caspases-3 and -7, but OfCasp3a (Orbicella faveolata caspase-3a) and PaCasp7a (Porites astreoides caspase-7a), which we show to be DXXDases, contain an N-terminal caspase activation/recruitment domain (CARD) similar to human initiator/inflammatory caspases. OfCasp3b (Orbicella faveolata caspase-3b) and PaCasp3 (Porites astreoides caspase-3), which we show to be VXXDases, have short pro-domains, like human executioner caspases. Our biochemical analyses suggest a mechanism in coral which differs from that of humans, where the CARD-containing DXXDase is activated on death platforms but the protease does not directly activate the VXXDase. The first X-ray crystal structure of a coral caspase, of PaCasp7a determined at 1.57 Å resolution, reveals a conserved fold and an N-terminal peptide bound near the active site that may serve as a regulatory exosite. The binding pocket has been observed in initiator caspases of other species. These results suggest mechanisms for the evolution of substrate selection while maintaining common activation mechanisms of CARD-mediated dimerization.

Development of an age-scalable 3D computational phantom in DICOM standard for late effects studies of childhood cancer survivors.

Purpose: We previously developed an age-scalable 3D computational phantom that has been widely used for retrospective whole-body dose reconstructions of conventional two-dimensional historic radiation therapy (RT) treatments in late effects studies of childhood cancer survivors. This phantom is modeled in the FORTRAN programming language and is not readily applicable for dose reconstructions for survivors treated with contemporary RT whose treatment plans were designed using computed tomography images and complex treatment fields. The goal of this work was to adapt the current FORTRAN model of our age-scalable computational phantom into Digital Imaging and Communications in Medicine (DICOM) standard so that it can be used with any treatment planning system (TPS) to reconstruct contemporary RT. Additionally, we report a detailed description of the phantom's age-based scaling functions, information that was not previously published. Method: We developed a Python script that adapts our phantom model from FORTRAN to DICOM. To validate the conversion, we compared geometric parameters for the phantom modeled in FORTRAN and DICOM scaled to ages 1 month, 6 months, 1, 2, 3, 5, 8, 10, 15, and 18 years. Specifically, we calculated the percent differences between the corner points and volume of each body region and the normalized mean square distance (NMSD) between each of the organs. In addition, we also calculated the percent difference between the heights of our DICOM age-scaled phantom and the heights (50th percentile) reported by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for male and female children of the same ages. Additionally, we calculated the difference between the organ masses for our DICOM phantom and the organ masses for two reference phantoms (from International Comission on Radiation Protection (ICRP) 89 and the University of Florida/National Cancer Institute reference hybrid voxel phantoms) for ages newborn, 1, 5, 10, 15 and adult. Lastly, we conducted a feasibility study using our DICOM phantom for organ dose calculations in a commercial TPS. Specifically, we simulated a 6 MV photon right-sided flank field RT plan for our DICOM phantom scaled to age 3.9 years; treatment field parameters and age were typical of a Wilms tumor RT treatment in the Childhood Cancer Survivor Study. For comparison, the same treatment was simulated using our in-house dose calculation system with our FORTRAN phantom. The percent differences (between FORTRAN and DICOM) in mean dose and percent of volume receiving dose ⩾5 Gy were calculated for two organs at risk, liver and pancreas. Results: The percent differences in corner points and the volumes of head, neck, and trunk body regions between our phantom modeled in FORTRAN and DICOM agreed within 3%. For all of the ages, the NMSDs were negliglible with a maximum NMSD of 7.80 × 10-2 mm for occiptital lobe of 1 month. The heights of our age-scaled phantom agreed with WHO/CDC data within 7% from infant to adult, and within 2% agreement for ages 5 years and older. We observed that organ masses in our phantom are less than the organ masses for other reference phantoms. Dose calculations done with our in-house calculation system (with FORTRAN phantom) and commercial TPS (with DICOM phantom) agreed within 7%. Conclusion: We successfully adapted our phantom model from the FORTRAN language to DICOM standard and validated its geometric consistency. We also demonstrated that our phantom model is representative of population height data for infant to adult, but that the organ masses are smaller than in other reference phantoms and need further refinement. Our age-scalable computational phantom modeled in DICOM standard can be scaled to any age at RT and used within a commercial TPS to retrospectively reconstruct doses from contemporary RT in childhood cancer survivors.

Prognostic significance of semi-quantitative FDG-PET parameters in stage I non-small cell lung cancer treated with carbon-ion radiotherapy.

PURPOSE: Prognostic significance of volumetric 18F-fluorodeoxyglucose (FDG) positron emission tomography/computer tomography (PET/CT) parameters in carbon-ion radiotherapy (C-ion RT) treated stage I non-small cell lung cancer, and need of histology-wise separate cut-off values for risk stratification were assessed. METHODS: Thirty-nine patients (29 men and 10 women, 71.9 ± 8.3 years) who underwent FDG PET/CT examinations before C-ion RT were retrospectively evaluated. FDG-PET parameters: standardized uptake values (SUVmax, SUVpeak, and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), and clinicopathological variables were assessed for prognosis using Cox proportional hazards regression analysis. Mann-Whitney test compared medians of significant parameters between adenocarcinoma (AC) and squamous cell carcinoma (SCC), and Kaplan-Meier curves were plotted for median-based low- and high-risk groups. RESULTS: Median follow-up period was 44.8 months. 1/2/3-year overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 94.9/84.3/70.8, 82.1/69.2/58.4 and 97.3/85.7/82.3%. Multivariate analysis revealed age (hazard ratio, HR: 1.09; 95% confidence interval, CI: 1.0-1.19, p < 0.05) and MTV (HR 4.83, 95% CI 1.21-19.27, p < 0.03) predicted OS, and only MTV predicted PFS (HR 5.3, CI 1.32-21.35, p < 0.02) independently. Compared with AC, SCC had higher MTV (median, 6.625cm3 vs 0.2 cm3, p < 0.01). Single MTV cut-off based on overall cohort was insignificant in SCC for PFS (p > 0.02); separate cut-offs of MTV, 0.2 cm3 for AC (p < 0.03) and 6.625 cm3 for SCC (p < 0.05) were relevant. CONCLUSION: Among all FDG PET/CT parameters, only MTV beared prognostic ability for stage I NSCLC treated with C-ion RT, and its histological variation may need consideration for risk-adapted therapeutic management.